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Molecular Basis of Incomplete O-Glycan Synthesis in MCF-7 Breast Cancer Cells: Putative Role of MUC6 in Tn Antigen Expression

¹ Laboratorio de Oncología Básica y Biología Molecular, Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay; ² Unité de Chimie Organique, URA Centre National de la Recherche Scientifique 2128, Institut Pasteur, Paris, France; and ³ Department of Obstetrics and Gynaecology, VU University Medical Centre, Amsterdam, the Netherlands

Requests for reprints: Eduardo Osinaga, Laboratorio de Oncología Básica y Biología Molecular, Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Avenida General Flores 2125 C.P. 11800 Montevideo, Uruguay. Phone: 598-29249562; Fax: 598-29249563; E-mail: eosinaga{at}fmed.edu.uy.

An incomplete elongation of O-glycan saccharide chains in mucins have been found in epithelial cancers, leading to the expression of shorter carbohydrate structures, such as the Tn antigen (GalNAc-O-Ser/Thr). This antigen is one of the most specific human cancer–associated structures and is capable of inducing effective immune responses against cancer cells. We aimed to investigate the causes of the expression of Tn antigen in the Tn-rich MCF-7 breast cancer cell line focusing on the first step of the O-glycosylation process. Interestingly, amino acid sequences derived from "nonmammary" apomucins (MUC5B and MUC6) were very good acceptor substrates for ppGalNAc-Ts, which are the enzymes catalyzing the Tn antigen synthesis. MUC6 peptide glycosylation with MCF-7 microsome extracts as source of ppGalNAc-T activity yielded 95% conversion of the peptide into MUC6-Tn. In addition, the MUC6-Tn glycopeptide was a poor acceptor substrate for core 1 ß3Gal-T, the next enzyme involved in the saccharide chain biosynthesis, yielding only 5% conversion of MUC6-Tn into MUC6-TF. These results indicate that nonmammary apomucin expression could be responsible, at least in part, for Tn antigen expression in MCF-7 breast cancer cells due to a combined action on glycosyltransferases: an increase of ppGalNAc-T activity and a decrease of core 1 ß3Gal-T activity. Our hypothesis is supported by experiments in vivo showing that (a) native MUC6 glycoproteins express the Tn antigen in MCF-7 cells and (b) Tn antigen expression is increased after transfection with a construct encoding for a MUC6 recombinant protein into the low Tn-expressing breast cancer cell T47D. These results open new horizons in breast cancer glycoimmunology, stressing the potential role of nonmammary apomucins.

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